Stero controlled synthesis of (e,z)-dienals via tandem rh(i) catalyzed propargyl claisen rearrangement

ABSTRACT

A novel Rh(I)-catalyzed approach to synthesizing functionalized (E,Z) dienal compounds has been developed via tandem transformation where a stereoselective hydrogen transfer follows a propargyl Claisen rearrangement. Z-Stereochemistry of the first double bond suggests the involvement of a six-membered cyclic intermediate whereas the E-stereochemistry of the second double bond stems from the subsequent protodemetallation step giving an (E,Z)-dienal. The reaction may be represented by the following sequence.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application claims priority from U.S. provisional Application No.62/011,251, filed Jun. 12, 2014, the disclosure of which is herebyincorporated by reference as if set forth in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant CHE-1152491awarded by the National Science Foundation. The Government has certainrights in the invention.

FIELD OF THE INVENTION

The present invention generally relates to a method for synthesizingfunctionalized (E,Z)-dienal compounds. More specifically, functionalized(E,Z)-dienal compounds are prepared by tandem transformation where astereoselective hydrogen transfer follows a propargyl Claisenrearrangement.

BACKGROUND OF THE INVENTION

Polyene motifs with (E,Z) stereochemistry are ubiquitous in biologicallyactive and naturally occurring systems. See (a) McGarvey, B. D.;Attygalle, A. B.; Starratt, A. N.; Xiang, B.; Schroeder, F. C.; Brandle,J. E.; Meinwald, J. Nat. Prod. 2003, 66, 1395. (b) Robinson, C. Y.;Waterhous, D. V.; Muccio, D. D.; Brouillette, W. J. Bioorg. Med. Chem.Lett., 1995, 5, 953. (c) Asfaw, N.; Storesund, H. J.; Skattebol, L.;Aasen A, J. Phytochemistry 1999, 52, 1491. (d) Hiraoka, H.; Mori, N.;Nishida, R.; Kuwahara, Y. Biosci. Biotechnol. Biochem., 2001, 65, 2749.(e) Matsumoto, H.; Asato, A. E.; Denny, M.; Baretz, B.; Yen, Y-P.; Tong,D.; Liu, R. S. H. Biochemistry, 1980, 19, 4589. Several naturalcompounds are shown below:

Accordingly, polyene motifs with (E, Z) stereochemistry representsynthetically important targets. See (a) Knowles, W. S. Angew. Chem.,Int. Ed. 2002, 41, 1998. Noyori, R. Angew. Chem., Int. Ed. 2002, 41,2008. (b) Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (c)Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3740. (d) Schrock, R. R.Angew. Chem., Int. Ed. 2006, 45, 374. (e) Grubbs, R. H. Angew. Chem.,Int. Ed. 2006, 45, 3760. Not only are synthetic routes to Z-alkenesrelatively limited but such traditional approaches to unsaturatedconjugated Z-polyenes as Wittig and Horner-Wadsworth-Emmons reactions,cannot be used to directly deliver unsaturated aldehydes. See (a) Smith,A. B III, Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.;Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122,8654. (b) Dong, D-J.; Li, H-H.; Tian, S-K. J. Am. Chem. Soc. 2010, 132,5018. (c) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.(d) Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313. (e)Huang, Z.; Negishi, E-I. J. Am. Chem. Soc. 2007, 129, 14788. (f)Belardi, J. K.; Micalizio, G. C. J. Am. Chem. Soc. 2008, 130, 16870. (g)Lindlar, H.; Dubuis, R. Org Synth. 1966, 46, 89. (h) Randl, S.; Gessler,S.; Wakamatsu, H.; Blechert, S. Synlett 2001, 430. (i) Kang, B.; Kim,D-H.; Do, Y.; Chang, S. Org. Lett. 2003, 5, 3041. (j) Hansen, E. C.;Lee, D. Org. Lett. 2004, 6, 2035. (k) Kang, B.; Lee, J, M.; Kwak, J.;Lee, Y. S.; Chang, S. J. Org. Chem. 2004, 69, 7661. (1) Sashuk, V.;Samojlowicz, C.; Szadkowska, A.; Grela, K. Chem Commun. 2008, 2468. (m)Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 5162.

The traditional metal-free approaches to unsaturated conjugatedZ-polyenes, which are relatively few such as Wittig andHornder-Wadsworth-Emmons reactions, cannot be used to directly deliverunsaturated aldehydes. The metal-catalyzed cross-coupling of twosp²-hybridized reactants requires activating functionalities (e.g.,organoboranes or organo-stannanes) which may be toxic, expensive and/ordeleterious for the overall atom efficiency. Methods for the directincorporation of the unsaturated α,β-carbonyl compounds with theZ-stereochemistry are limited. See (a) Maynard, D. F.; Okamura, W. H. J.Org. Chem. 1995, 60, 1763. (b) Duhamel, L.; Guillemont, J.; Poirier,J-M. Tetrahedron Lett. 1991, 32, 4495. (c) Cahard, D.; Duhamel, L.;Lecomte, S.; Poirier, J-M. Synlett 1998, 12, 1399. (d) Amos, R. A.;Katzenellenbogen, J. A. J. Org. Chem. 1978, 43, 555.

The metal-catalyzed Claisen rearrangement offers new mechanistic pathsto this classic reaction and significantly expands its syntheticutility. See (a) Tejedor, D.; Mendez-Abt, G.; Cotos, L.; Garcia-Tellado,F. Chem. Soc. Rev., 2013, 42, 458. Aluminium: (b)Bates, D. K.; Janes, M.W. J. Org. Chem. 1978, 43, 3856. (c) Majumdar, K. C.; Chattopadhyay, B.Synth. Commun. 2006, 36, 3125. (d) Majumdar, K. C.; Islam, R. J.Heterocycl. Chem. 2007, 44, 871. (e)Majumdar, K. C.; Islam, R. Can. J.Chem. 2006, 84, 1632. (f) Majumdar, K. C.; Bhattacharyya, T. TetrahedronLett. 2001, 42, 4231. (g) Majumdar, K. C.; Ghosh, M.; Jana, M.; Saha, D.Tetrahedron Lett. 2002, 43, 2111. (h) Majumdar, K. C.; Bandyopadhyay,A.; Biswas, A. Tetrahedron 2003, 59, 5289. Cu(II), Sn(IV), Ti(IV) andLa(III): (i)Takanami, T.; Hayashi, M.; Suda, K. Tetrahedron Lett. 2005,46, 2893. (j) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000,122, 3785. (k) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem.Soc. 2000, 122, 8131. (1) Nasveschuk, C. G.; Rovis, T. Org. Lett. 2005,7, 2173. (m) Nasveschuk, C. G.; Rovis, T. Angew. Chem., Int. Ed. 2005,44, 3264. (n) Kaden, S.; Hiersemann, M. Synlett 2002, 1999. (o)Helmboldt, H.; Hiersemann, M. Tetrahedron 2003, 59, 4031. (p) Abraham,L.; Korner, M.; Hiersemann, M. Tetrahedron Lett. 2004, 45, 3647. (q)Sharghi, H.; Aghapour, G. J. Org. Chem. 2000, 65, 2813. (r) Bancel, S.;Cresson, P. C. R. Acad. Sci. Ser. C. 1970, 270, 2161. (s) Nonoshita, K.;Banno, H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316.(t) Sugiura, M.; Nakai, T. Chem. Lett. 1995, 697. (u)Akiyama, K.;Mikami, K. Tetrahedron Lett. 2004, 45, 7217. (v) Itami, K.; Yamazaki,D.; Yoshida, J. Org. Lett. 2003, 5, 2161. (w) Jamieson, A. G.;Sutherland, A. Org. Biomol. Chem. 2006, 4, 2932. (x)Swift, M. D.;Sutherland, A. Org. Biomol. Chem. 2006, 4, 3889. (y) Nakamura, I.;Bajracharya, G. B.; Yamamoto, Y. Chem. Lett. 2005, 34, 174. (z)Sattelkau, T.; Eilbracht, P. Tetrahedron Lett. 1998, 39, 1905. (aa)Eilbracht, P.; Gersmeier, A.; Lennard, D.; Huber, T. Synthesis 1995,330; (ab) Sattelkau, T.; Hollmann, C.; Eilbracht, P. Synlett 1996,1221.(ac) Sattelkau, T.; Eilbracht, P. Tetrahedron Lett. 1998, 39, 9647.

When metals coordinate with π-bases, such as alkenes or alkynes, thefirst step of the rearrangement can be described as a 6-endo-digcyclization that leads to a cyclic six-membered intermediate (See FIG.1). Thus, this mode of rearrangement was termed “cyclization-mediatedpathway”. See (a) Henry, P. M. Acc. Chem. Res. 1973, 16. (b) Henry, P.M. Adv. Organomet. Chem. 1975, 13, 363. (c) Overman, L. E. Angew. Chem.lnt. Ed. Engl. 1984, 23, 579. On the other hand, Lewis acids, such asCu⁺², Al⁺³ and H+ initiate the so-called “cation-accelerated oxoniaClaisen” rearrangement by coordinating with oxygen (See FIG. 1). See (a)Maruoka, K.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117, 1165.(b) Stevenson, J. W. S.; Bryson. Tetrahedron Lett. 1982, 23, 3143. (c)Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1984,57, 446. (d) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron1984, 40, 4013. (e) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H.Tetrahedron Lett. 1981, 22, 3985.

Recently, we reported a mechanistic study of Au(I)-catalyzed propargylClaisen and allenyl vinyl ether rearrangement, where Au(I), commonlyconsidered as an alkynophilic Lewis acid, coordinates with the oxygenand directs the Claisen rearrangement through an oxonia path. See (a)Vidhani, D. V.; Cran, J. W.; Krafft, M. E.; Manoharan, M.; Alabugin, I.V. J. Org. Chem. 2013, 78, 2059. (b) Vidhani, D. V.; Cran, J. W.;Krafft, M. E.; Alabugin, I. V. Org. Biomol. Chem., 2013, 11, 1624. Thebarrier for the alternative cyclization-mediated pathway is 1.5 kcal/molhigher. Two important features of the calculated Au-catalyzedcyclization-mediated pathway includes: 1) lack of substituent effectsand 2) selective stabilization of the TS for the Grob fragmentation ofthe six-membered intermediate by Au(I)-catalysts.

The latter effect lowers the barrier to the extent that thisintermediate corresponds to a shallow inflection on the potential energysurface, so the overall process blends the characteristics of a stepwiseand a concerted process. The nature of this unusual potential energysurface depends strongly on substrate-catalyst coordination and solvent,as illustrated by the successful trapping of the six-memberedintermediate by nucleophilic attack of water in dioxane reported by theToste group. See (a) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste,D. J. Am. Chem. Soc. 2006, 128, 8132.

SUMMARY OF THE INVENTION

The present invention is directed to the transformation of propargylvinyl ethers into (E,Z)-dienal compounds using a Rh(I)-catalyzedpropargyl Claisen rearrangement and prototropic isomerization sequence.

In one preferred embodiment, shown below, the method of the presentinvention provides α,β-unsaturated aldehydes from starting reactantscomprising a functionalized aldehyde and a functionalized alkyne inthree steps with excellent stereoselectivity:

In some specific embodiments, the present invention is directed to areaction sequence in which the reactants, products of each step, andreaction conditions of each step are as shown below. Starting reactantsmay include the following functionalized aldehyde and functionalizedacetylide:

In some embodiments, the functionalized acetylide may be formed fromreaction of a strong base with a functionalized alkyne. Suitableconditions for the reaction between the functionalized aldehyde and thefunctionalized acetylide include THF as the solvent at 0° C. or −78° C.for between 1 and 2 hrs.

In some embodiments, the product of the first step and the reactant forthe second step is a functionalized propargyl, which may have thefollowing structure:

In some embodiments, the product of the second step and the reactant forthe third step is a functionalized propargyl vinyl ether, which may havethe following structure:

In some embodiments, suitable conditions for this reaction include 0.6%Hg(OAc)₂ catalyst in a concentration of 0.2 M in a solvent of Ethylvinyl ether for between 12 and 16 hrs reflux.

In some embodiments, the functionalized propargyl vinyl ether reactantfrom above may undergo Rh(I) catalyzed Tandem rearrangement from afunctionalized allene-aldehyde compound to a functionalized (E,Z)-dienalcompound, having the structures as shown below:

The above is one non-limiting exemplary embodiment of the method of thepresent invention.

Accordingly, among the provisions of the present invention may be notedis a method to synthesize an (E,Z)-dienal compound having structure (V).The method comprises contacting a compound having structure (III) with acatalyst comprising Rh(I) to thereby prepare the compound havingstructure (V); wherein the compounds having structures (III) and (V)have the following structures:

In the above structures, R₁ is selected from the group consisting ofC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino;and R₂ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino

The present invention is further directed to a method to synthesize an(E,Z)-dienal compound having structure (V). The method comprisescontacting a compound having structure (IV) with a catalyst comprisingRh(I) to thereby prepare the compound having structure (V);

In the above structures, R₁ is selected from the group consisting ofC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino;and R₂ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino.

The present invention is still further directed to a method of preparinga compound having structure (III). The method comprises contacting acompound having structure (I) and a compound having structure (II) inthe presence of a strong base; wherein the compounds having structures(I), (II), and (III) have the following structures:

In the above structures, R₁ is selected from the group consisting ofC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino;and R₂ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino.

The present invention is still further directed to a method tosynthesize an allene-aldehyde compound having structure (IV). The methodcomprises contacting a compound having structure (III) with a catalystcomprising Rh(I) to thereby prepare the compound having structure (IV);wherein the compounds having structures (III) and (IV) have thefollowing structures:

In the above structures, R₁ is selected from the group consisting ofC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino;and R₂ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino.

Other objects and features will be in part apparent and in part pointedout hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts three mechanistic alternatives for the metal-catalyzedpropargyl Claisen rearrangement. Cyclization-mediated pathway depictedon left shows two possibilities emerging from the six-membered cyclicintermediate.

FIG. 2 depicts the proposed catalytic cycle. ΔE values correspond to thePCM-SCRF-M05-2X/LANL2DZ energies of the intermediate species relative tothe uncomplexed Rh(I)-dimer.

FIG. 3 illustrates Curtin-Hammett analysis of the three mechanisms.Energies in toluene were calculated at the PCM-SCRF-M05-2X/LANL2DZ levelon the gas phase optimized geometries.

DETAILED DESCRIPTION OF THE EMBODIMENT(S) OF THE INVENTION

The present invention is directed to an efficient process to installsynthetically challenging (E,Z) conjugated double bond in three stepsstarting from a precursor aldehyde and a precursor alkyne with a veryhigh stereoselectivity. The first two steps are high yielding reactionleading to the formation of a propargyl vinyl ether. The last step is atandem process which can be interrupted to give an allene-aldehydecompound or allowed to continue to give a (E,Z)-dienal compound. Thismethod is general for aromatic and tertiary aldehydes.

In some embodiments, the method of the present invention may berepresented by the following reaction sequence:

The present invention is directed to a novel Rh(I)-catalyzed approach tofunctionalized (E, Z) dienal compounds via tandem transformation where astereoselective hydrogen transfer follows a propargyl Claisenrearrangement. Z-Stereochemistry of the first double bond suggests theinvolvement of a six-membered cyclic intermediate whereas theE-stereochemistry of the second double bond stems from the subsequentprotodemetallation step giving an (E,Z)-dienal.

The combination of experiments and computations reveals unusual featuresof stereoselective Rh(I)-catalyzed transformation of propargyl vinylethers into (E, Z)-dienals. The first step, the conversion of propargylvinyl ethers into allene aldehydes, proceeds under homogeneousconditions via the “cyclization-mediated” mechanism initiated by Rh(I)coordination at the alkyne. This path agrees well with the smallexperimental effects of substituents on the carbinol carbon. The keyfeature revealed by the computational study is the stereoelectroniceffect of the ligand arrangement at the catalytic center. Therearrangement barriers significantly decrease due to the greatertransfer of electron density from the catalytic metal center to the COligand oriented trans to the alkyne. This effect increaseselectrophilicity of the metal and lowers the calculated barriers by 9.0kcal/mol. Subsequent evolution of the catalyst leads to the in-situformation of Rh(I)-nanoclusters which catalyze stereoselectivetautomerization. The intermediacy of heterogeneous catalysis bynanoclusters was confirmed by mercury poisoning, temperature-dependentsigmoidal kinetic curves, and dynamic light scattering. The combinationof experiments and computations suggest that the initially formedallene-aldehyde product assists in the transformation of a homogeneouscatalyst (or “a cocktail of catalysts”) into nanoclusters, which, inturn, catalyze and control the stereochemistry of subsequenttransformations.

In some embodiments, the method of the present invention comprises thesynthesis of the propargyl vinyl ether having structure (III), asdepicted below:

In structure (III), R₁ may be selected from the group consisting ofC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, amino, or C₁₋₁₂ alkylamino.The alkyl, aryl, cycloalkenyl, heteroaryl, amino, and alkylamino groupsmay be unsubstituted. The alkylamino may be primary, secondary, ortertiary. In some embodiments, the alkyl, aryl, cycloalkenyl,heteroaryl, amino, and alkylamino groups may be substituted. Suitablesubstituents include C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halogen(i.e., fluoro, chloro, bromo, iodo), hydroxy, cyano, C₁₋₁₂ alkoxy,nitro, sulfinyl, sulfonyl, amino, or C₁₋₁₂ alkylamino. The alkylaminosubstituent may be primary, secondary, or tertiary.

In some preferred embodiments, R₁ comprises a C₆₋₂₄ aryl or C₃₋₁₈heteroaryl, which may be unsubstituted or may be further substitutedwith any of the above described moieties. Suitable substituents includeC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halogen (i.e., fluoro,chloro, bromo, iodo), hydroxy, cyano, C₁₋₁₂ alkoxy, nitro, sulfinyl,sulfonyl, amino, or C₁₋₁₂ alkylamino.

In structure (III), R₂ may be selected from the group consisting ofC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, amino, or C₁₋₁₂ alkylamino.The alkyl, aryl, cycloalkenyl, heteroaryl, amino, and alkylamino groupsmay be unsubstituted. The alkylamino may be primary, secondary, ortertiary. In some embodiments, the alkyl, aryl, cycloalkenyl,heteroaryl, amino, and alkylamino groups may be substituted. Suitablesubstituents include C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂cycloalkyl, C₁₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halogen(i.e., fluoro, chloro, bromo, iodo), hydroxy, cyano, C₁₋₁₂ alkoxy,nitro, sulfinyl, sulfonyl, amino, or C₁₋₁₂ alkylamino. The alkylaminosubstituent may be primary, secondary, or tertiary.

In some preferred embodiments, R₂ comprises a C₆₋₂₄ aryl or C₃₋₁₈heteroaryl, which may be unsubstituted or may be further substitutedwith any of the above described moieties. Suitable substituents includeC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halogen (i.e., fluoro,chloro, bromo, iodo), hydroxy, cyano, C₁₋₁₂ alkoxy, nitro, sulfinyl,sulfonyl, amino, or C₁₋₁₂ alkylamino.

In some embodiments, R₁ and R₂ may be the same. In some embodiments, R₁and R₂ may be different.

In the context of the present specification, unless otherwise stated, analkyl substituent group or an alkyl moiety in a substituent group may belinear or branched. Examples of C₁₋₁₂ alkyl groups/moieties includemethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl,n-pentyl, iso-pentyl, neopentyl, n-hexyl, isohexyl, neohexyl, n-heptyl,isoheptyl, neoheptyl, n-octyl, isooctyl, neooctyl, n-nonyl, n-decyl,n-undecyl, n-dodecyl, etc. The substituent group may comprise a doublebond, e.g., C₂₋₁₂ alkenyl, a triple bond, e.g., C₂₋₁₂ alkynyl, or maycomprise more than one double bond.

In the context of the present specification, unless otherwise stated, analkoxy substituent group or an alkoxy moiety in a substituent group maybe linear or branched. Examples of C₁₋₁₂ alkoxy groups/moieties includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,tert-butoxy, n-pentoxy, iso-pentoxy, neopentoxy, n-hexoxy, etc.

In the context of the present specification, unless otherwise stated, ahydroxyalkyl substituent group or a hydroxyalkyl moiety in a substituentgroup may be linear or branched. Examples of C₁₋₆ hydroxyalkylgroups/moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, tert-butyl, n-pentyl, n-hexyl, etc, each of which comprisesat least one hydroxyl group substituent in place of a hydrogen.

Halogen or halo encompasses fluoro, chloro, bromo, and iodosubstituents.

In the context of the present specification, cycloalkyl is anon-aromatic ring that can comprise one, two or three non-aromaticrings, and is, optionally, fused to a benzene ring (for example to forman indanyl, or 1,2,3,4-tetrahydronaphthyl ring). Cycloalkyl may comprisefrom 3 to 12 carbon atoms. Examples of cycloalkyl include cycobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,cyclopentenyl, cyclohexenyl, or adamantly, among others.

In the context of the present specification, cycloalkenyl is anon-aromatic ring that can comprise one, two or three non-aromaticrings, and is, optionally, fused to a benzene ring (for example to forman indanyl, or 1,2,3,4-tetrahydronaphthyl ring). Cycloalkenyl maycomprise from 3 to 12 carbon atoms. Examples of cycloalkenyl includecyclopropenyl, cycobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, etc.

In the context of the present invention, aryl encompasses aromaticrings, which may be fused or unfused to other aromatic or cycloalkylrings. Aryl may comprise from 6 to 24 carbon atoms. Examples or arylinclude benzene, naphthalene, acenaphthene, anthracene,benz[a]anthracene, benzo[a]pyrene, benzo[e]pyrene, chrysene,indeno(1,2,3-cd)pyrene, phenanthrene, pyrene, coronene, fluorene, andthe like.

In the context of the present specification, heterocyclic ring is anaromatic or non-aromatic ring having from three to eight total atomsforming the ring system. The atoms within the ring system comprisecarbon and at least one of nitrogen, sulfur, and oxygen. A heterocyclicring may be fused to a homocyclic ring or another heterocyclic ring. Thefused ring system may be aromatic or non-aromatic. Heteroaryl maycomprise from 3 to 24 carbon atoms. Examples include aziridine, azirine,oxirane, oxirene, thirane, thiirene, azetidine, azete, oxetane, oxete,thietane, thiete, diazetidine, dioxetane, dioxete, dithietane, dithiete,pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene,imidazolidine, imidazole, pyrazolidine, pyrazole, oxasolidine, oxazole,isoxazolidine, isoxazole, piperidine, pyridine, oxane, pyran, thiane,thiopyran, piperazine, diazines, morpholine, oxazine, etc.

In some embodiments, the compound having structure (III) may synthesizedby contacting a compound having structure (I) and a compound havingstructure (II) according to the following sequence:

wherein R₁ and R₂ are as defined above with respect to Structure (III).

The reaction occurs in the presence of a strong base. Suitable strongbases for use in the method of the present invention includeorganolithium compounds, including alkyl lithium compounds, such asn-butyl lithium, sec-butyl lithium, isopropyl lithium, etc., or aGrignard reagent, such as an organomagnesium halide. The n-butyl lithiummay be provided in an alkane (e.g., pentane, hexane, heptane) solutionor in an ether (e.g., diethyl ether, tetrahydrofuran) solution.

In some embodiments, the structure (III) may synthesized by contacting acompound having structure (I) and a compound having structure (II)according to the following sequence:

wherein R₁ and R₂ are as defined above with respect to Structure (III).

According to some embodiments of the method of the present invention, acompound having structure (III) is contacted with a catalyst comprisingRh(I) to thereby prepare an (E,Z)-dienal compound having structure (V):

wherein R₁ and R₂ are as defined above with respect to Structure (III).

According to some embodiments of the method of the present invention,the compound having structure (III) is contacted with a catalystcomprising Rh(I) in order to prepare a compound having structure (IV):

wherein R₁ and R₂ are as defined above with respect to Structure (III).In some embodiments of the method of the present invention, the compoundhaving structure (IV), i.e., a compound comprising allene-aldehyde, maybe isolated. In some embodiments of the method of the present invention,the compound having structure (IV), i.e., a compound comprisingallene-aldehyde may undergo further rearrangement into the compoundhaving structure (V).

According to some embodiments of the method of the present invention, acompound having structure (IV) is contacted with a catalyst comprisingRh(I) to thereby prepare an (E,Z)-dienal compound having structure (V):

wherein R₁ and R₂ are as defined above with respect to Structure (III).

Applicable Rhodium(I) catalysts includeAcetylacetonatobis(ethylene)rhodium(I) 95%,(Acetylacetonato)(1,5-cyclooctadiene)rhodium(I) 99%,(Acetylacetonato)(1,5-cyclooctadiene)rhodium(I) 99%,(Acetylacetonato)(1,5-cyclooctadiene)rhodium(I) 99%,(Acetylacetonato)dicarbonylrhodium(I) 98%,(Acetylacetonato)dicarbonylrhodium(I) 98%,(Acetylacetonato)(norbornadiene)rhodium(I),(Bicyclo[2.2.1]hepta-2,5-diene)[1,4-bis(diphenylphosphino)butane]rhodium(I)tetrafluoroborate, Bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloridedimer 96%, Bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloride dimer,Bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate,[(Bisacetonitrile)(norbornadiene)]rhodium(I) hexafluoroantimonate 97%,Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate hydrate 97%,Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate hydrate,Bis(1,5-cyclooctadiene)rhodium(I) hexafluoroantimonate 97%,Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate,Bis(1,5-cyclooctadiene)rhodium(I)tetrakis[bis(3,5-trifluoromethyl)phenyl]borate,Bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate 98%,Bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate,1,1′-Bis(diisopropylphosphino)ferrocene(cod)Rh-phosphotungstic acid onsilica gel 100-200 mesh, extent of labeling: 0.020 mmol/g Rh loading,Bis[(10,11-η)-5-[(11bS)-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-yl-κP⁴]-5H-dibenz[b,f]azepine]rhodium(I)tetrafluoroborate salt 97%,[1,4-Bis(diphenylphosphino)butane](1,5-cyclooctadiene)rhodium(I)tetrafluoroborate 98%, Bis(norbornadiene)rhodium(I) tetrafluoroborate,Bis(norbornadiene)rhodium(I) trifluoromethanesulfonate 97%,Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] 96%,Bis(triphenylphosphine)rhodium(I) carbonyl chloride 99.9%,Chlorobis(cyclooctene)rhodium(I),dimer 98%,Chloro[bis[(10,11-η)-5H-dibenzo[a,d]cyclohepten-5-yl]amine-κN]rhodium(I)dimer, Chloro(1,5-cyclooctadiene)rhodium(I) dimer 98%,Chloro(1,5-hexadiene)rhodium(I),dimer 98%,Chlorotris[3,3′,3″-phosphinidynetris(benzenesulfonato)]rhodium(I)nonasodium salt hydrate 99%,(1,5-Cyclooctadiene)bis(triphenylphosphine)rhodium(I)hexafluorophosphate dichloromethane complex (1:1),(1,5-Cyclooctadiene)(8-quinolinolato)rhodium(I) 97%,Dicarbonyl(pentamethylcyclopentadienyl)rhodium(I) 99%,Di-μ-chloro-tetracarbonyldirhodium(I) 97%, Di-μ-chlorotetraethylenedirhodium(I), Dirhodium tetracaprolactamate 97%, Hexarhodium(0)hexadecacarbonyl Rh 57-60% (approx.),Hydridotetrakis(triphenylphosphine)rhodium(I),Hydroxy(cyclooctadiene)rhodium(I) dimer 95%,Methoxy(cyclooctadiene)rhodium(I) dimer,Triphenylphosphine(2,5-norbornadiene)rhodium(I) tetrafluoroborate,polymer-bound Fibre-Cat®,[Tris(dimethylphenylphosphine)](2,5-norbornadiene)rhodium(I)hexafluorophosphate 97%, Tris(triphenylphosphine)rhodium(I) carbonylhydride 97%, Tris(triphenylphosphine)rhodium(I) chloride 99.9% tracemetals basis, Tris(triphenylphosphine)rhodium(I) chloride, andTris(triphenylphosphine)rhodium(I) chloride polymer-bound ˜1% Rh.

Suitable Rh(I) catalysts include di-μ-chloro-tetracarbonyldirhodium(I)[Rh(CO)₂Cl]z, Bis(triphenylphosphine)rhodium(I) carbonyl chloride,tris(triphenylphosphine)rhodium (I) carbonyl hydride,tris(triphenylphosphine)rhodium (I) carbonyl chloride, among other Rh(I)catalysts.

The most unusual feature of this invention is the generation of in-situRh(I)-nanoclusters which catalyzes the stereoselective isomerization ofallene-aldehyde. The onset of isomerization does not occur until thecomplete conversion of substrate, propargyl vinyl ether, into theallene-aldehyde intermediate. This is the first example of a shift fromhomogeneous to heterogeneous catalysis in one pot. Thus, therearrangement can either be stopped at the homogeneous step to isolateallene-aldehyde or allowed to continue under heterogeneous conditions togive (E, Z) dienal with high stereoselectivity.

To verify the involvement of Rh(I)-nanoclusters in the prototropicrearrangement, we performed dynamic light scattering (DLS) experimentson the allene-aldehyde derived from the phenyl substituted substrate 2(See Table 3). This technique is used to determine the size-distributionof particles in suspension. Typically, in the DLS experiment, thesolution containing the nanoclusters is irradiated with themonochromatic light from the laser and the intensity of the lightdiffracted by the nanocluster is measured. Since the scattered lightfrom nanoclusters undergoes constructive and destructive interference bythe surrounding scatterers, a complex intensity fluctuation patterncontaining a detailed information about the time scale of the movementof the scatterers emerges. To process this information, a mathematicaltool called autocorrelation, is used to identify a repeating patternburried under the complex signal.

${g^{2}\left( {q;\tau} \right)} = \frac{\langle{{I(t)}{I\left( {t + \tau} \right)}}\rangle}{{\langle{I(t)}\rangle}^{2}}$g²(q; τ):  Autocorrelation  function q:  Wave  vectorτ:  Delay  time I:  Intensity

Generally, data is interpreted only when the plot of intensity vs. timeshows a smooth and continuous decay of intensity for autocorrelationfunction. Such plots are classified as “proceed-category”. In thepresent study, the catalyst and the substrate solutions did not show thepresence of nanoclusters. Interestingly, the reaction mixture at 50%conversion of allene-aldehyde into respective (E, Z)-dienal (Error!Reference source not found.), showed the presence of 170 nmnanoclusters. Moreover, low observed polydispersity (5%) suggested thatthe solution consisted of uniformly sized particles.

Accordingly, experimental and computational analysis of the tandemprocess suggests a cascade transformation that evolves from homogeneousto heterogeneous catalysis. The Rh(I)-catalyzed propargyl Claisenrearrangement involves homogeneous catalysis whereas the subsequentprototropic rearrangement shows the telltale signs of heterogeneouscatalysis.

In this work, we disclose a tandem transformation of propargyl vinylethers into dienals, where stereochemistry at both double bonds in theproduct is defined simultaneously by the nature of a common cyclicintermediate located at the Claisen rearrangement hypersurfaceconnecting propargyl vinyl ethers with allene-aldehyde. Trapping of suchcyclic structure via deprotonation coupled with the Grob fragmentationshould lead to the conjugated dienals with E,Z-stereochemistry: theZ-geometry at the α,β-alkene is defined by the syn arrangement of theendocyclic σ-bonds whereas the E-stereochemistry at γ,δ-alkene stemsfrom the syn-arrangement of the exocyclic C-R1 and C-M bonds andproto-demetallation with retention of configuration. See the followinggeneral reaction sequence:

The (E, Z)-dienal only starts to form after the complete conversion ofpropargyl vinyl ether into the allene-aldehyde. Accordingly,intermediate (IV) can be isolated without proceeding to themetal-catalyzed propargyl Claisen rearrangement into the (E, Z)-dienalhaving structure (V). The mechanism of the six-membered intermediate inthe metal-catalyzed propargyl Claisen rearrangement into (E, Z)-dienalsdefines stereochemistry in both double bonds of the product is thoughtto proceed as follows:

Au(I)-catalyzed Claisen rearrangements of propargyl and allenyl vinylethers were first reported by the groups of Toste and Krafft,respectively. See Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004,126, 15978. (b) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem.Soc. 2009, 131, 4513; and Krafft, M. E.; Hallal, K. M.; Vidhani, D. V.;Cran, J. W. Org. Biomol. Chem., 2011, 9, 7535. In a recent mechanisticstudy of these two rearrangements, we found that although the cyclicintermediate does not correspond to an energy minimum at the DFTpotential energy hypersurface in the presence of R₃PAuShF₆-catalyst, thedetails of Au′ substrate interactions at this stage suggest that slightmodification in the nature of the catalyst may be sufficient forcreating and trapping such cyclic structure. See (a) Vidhani, D. V.;Cran, J. W.; Krafft, M. E.; Manoharan, M.; Alabugin, I. V. J. Org. Chem.2013, 78, 2059; (b) Vidhani, D. V.; Cran, J. W.; Krafft, M. E.;Alabugin, I. V Org. Biomol. Chem., 2013, 11, 1624; and (c) Sherry, B.D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006,128, 8132.

Although trapping via deprotonation has not been reported so far and ourinitial attempts with weak bases such as aniline led to deactivation ofthe Au-catalyst, we were further encouraged by the results of Toste andcoworkers who found that the use of multinuclear Au-catalyst providesaccess to such cyclic structure trappable by reaction with externalnucleophiles.

Because the equilibrium between the metal-alkyne, metal-vinyl ether andmetal-oxygen complexes should strongly depend on the nature of metal, wescanned a number of transition metal catalysts. Herein, we report thatstereoselective tandem isomerization of propargyl vinyl ethers to(E,Z)-dienals can be achieved using Rh(I)-catalysis.

Screening of commonly used transition metals showed that Au-basedcatalysts promote the Claisen rearrangement step but only AuCl isefficient in moving the cascade further (Table 1). However, thestereoselectivity of the final step was, at best, modest. Pd-basedcatalysts were only successful in promoting the first step. The hardLewis acids such as Cu(OTf)₂, Zn(OTf)₂ and Sc(OTf)₃ were even lessefficient. On the other hand, [Rh(CO)₂Cl]₂ displayed remarkablereactivity, effectively promoting both the allene formation and itssubsequent rearrangement into the desired (E,Z)-dienal 2a (Table 1,entry 14). Donor phosphine ligands at the Rh center eliminated thecatalytic activity (entry 15).

TABLE 1 Catalyst screening

entry catalyst 1 2a 2b 1 AuCl —^(b) 28 72 2 AuCl₃  72  9 17 3 Ph₃PAuSbF₆ 93  4  3 4 [Au]SbF₆ 100 — — 5 IPr-AuSbF₆ 100 — — 6 PdCl₂  12 — — 7Pd(PPh₃)₂Cl₂ 100 — — 8 Pd(PPh₃)₄  8  3 — 9 Pd(PhCN)₂Cl₂ 100 — — 10 PtCl₂— — — 11 Cu(OTf)₂  16 — — 12 Zn(OTf)₂  15 — — 13 Sc(OTf)₃   10^(c) — —14 [Rh(CO)₂Cl]₂ —^(b) 98  2 15 (PPh₃)₃RhCl — — — ^(a)Standard reactionconditions: 0.1M Substrate in toluene-d8 at 50° C. in the presence of10% metal catalyst for 24 hours. Ratios determined by proton NMR.^(b)Complete conversion of substrate into 1 was observed, followed byits full transformation into 2a and 2b.

Remarkably, [Rh(CO)₂Cl]₂ and AuCl provided cascade products in highyields but with the opposite stereochemistry. Table 2 summarizes furtheroptimization of the Rh-catalyzed reactions. Coordinating solvents suchas acetonitrile form a strong complex with Rh(I) and deactivate thecatalyst. See (a) Costa, M.; Della Pergola, R.; Fumagalli, A.; Laschi,F.; Losi, S.; Macchi, P.; Sironi, A.; Zanello, P. Inorg. Chem., 2007,46, 552. (b) Fumagalli, A.; Martinengo, S.; Ciani, G.; Moret, M.; SironiA. Inorg. Chem. 1992, 31, 2900. Rearrangement in the mildly coordinatingCH₂Cl₂ was sluggish (10% dienal 2a and 35% allene-aldehyde 1). Thereaction in tetrahydrofuran gave 90% allene-aldehyde 1 at the roomtemperature and proceeded slowly towards the 3:1 mixture of the dienalsat 50° C.

TABLE 2 Optimization studies entry solvent temp 1 2a 2b 1 CD₃CN 25 N.R —— 2 CD₃CN 50 N.R — — 3 CD₃NO₂ 25 Trace^(c) — — 4 THF-d₈ 25 90 — — 5THF-d₈ 50 89 8 3 6 CD₂Cl₂ 25 35 10 — 8 Toluene-d₈ 25 100 — — 7Toluene-d₈ 50 —^(b) 98 2 8 C₆D₆ 25 95 — — 9 C₆D₆ 50 —^(b) 95 5^(a)Standard reaction conditions: All reactions were performed at 0.1Mconcentration in the presence of 10% [Rh(CO)₂Cl]₂. Relative ratios weredetermined by proton NMR. ^(b)Complete conversion of enol ether into 1was observed that was subsequently fully converted into 2a and 2b.^(c)Significant decomposition of substrate was observed.

On the other hand, conversions in benzene and toluene were clean andproceeded in high yield and remarkable E,Z-selectivity for substrateswith the broad range of aromatic substituents at the carbinol carbon.Both donors and acceptors work well. Furthermore, other sp²-substituentsare also compatible with the cascade. For example, a cyclohexenylsubstituted substrate gave dienal product in 62% yield with excellent(E,Z)-stereoselectivity. Furthermore, the cascade tolerates sterichindrance—even with the bulky substituents such as t-butyl and mesityl,the Claisen products are quickly formed at 50° C. and smoothly convertedto the dienals in ˜80% yield and excellent stereoselectivity uponfurther heating.

The following Table 3 provides examples of starting propargyl vinylethers with products that may be obtained therefrom. The presentinvention is not limited to this list of propargyl vinyl ethers andtheir subsequent (E,Z)-dienal compounds, but rather, the method may besuitable for preparing a broad array of (E,Z)-dienal compounds.

TABLE 3 List of substrates used for the kinetic study. Substrate Product

  (1a)

  (1)

  (2a)

  (2)

  (3a)

  (3)

  (4a)

  (4)

  (5a)

  (5)

In some embodiments, the following exemplary compounds provided in Table4 may be prepared by the method of the present invention. The presentinvention is not limited to this list of compounds, but rather, themethod may be suitable for preparing a broad array of (E,Z)-dienalcompounds.

TABLE 4 Products of Rh(I)-catalyzed rearrangements obtained from theirrespective propargyl vinyl ethers.

2a

3

4

5

6

7

8

9

10

11

12

13Percentages correspond to the isolated yields. In the above list ofproducts, values in parenthesis show percentage of E,Z isomer determinedby proton NMR. ^(a)Reaction Conditions: 0.1 M solution of 0.1 mmolpropargyl vinyl ether in toluene in the presence of 10% [Rh(CO)₂Cl]₂ at50° C.^(b) Rearranges further into a mixture of products. ^(c) Requires70° C.

The current limitations of this process seem to be associated with thepossibility of further prototropic isomerizations. For substrates with an-butyl group at the carbinol carbon, the dienal yields decreases to˜50% due to formation of several non-identified non-polar by-products.In the presence of a secondary (cyclohexyl) substituent, formation ofClaisen product proceeded efficiently (>90%) at 50° C. but itssubsequent rearrangement at 70° C. produced only a small amount of (E,Z) dienal product together with unknown non-polar products. Thecyclopropyl-substituted substrate was unreactive in the presence ofRh(I) at 50° C. and decomposed at higher temperatures.

DFT calculations at the M05-2X/LANL2DZ level suggest that the electronrich vinyl ether dissociates 16 electron Rh(I)-dimer to form a 16electron Rh(I)-VE complex which is expected to be the catalyst restingstate. See FIG. 2. The uncomplexed monomeric 14 electron pre-catalyst,Rh(CO)₂Cl is unlikely to be persistent. See Pitcock, Jr, W. H.; Lord, R.L.; Baik, M-H. J. Am. Chem. Soc. 2008, 130, 5821.

Additional information regarding the mechanism of this isomerization wasprovided by DFT calculations. They revealed that the most stable complexproduced via coordination of Rh(I) with the vinyl ether is catalyticallyunproductive due to high barrier (FIG. 2, TS1: 41.2 kcal/mol). DFTcomputations performed at M05-2X level suggests that the less stablecomplexes formed via coordination of Rh(I) with the alkyne or the oxygenrearrange via considerably lower barriers. See (a) Zhao, Y.;Gonzalez-Garcia, N.; Truhlar, D. G. J. Phys. Chem. A 2005, 109, 2012.(b) Zhao, Y.; Truhlar, D. G. Org. Lett. 2007, 9, 1967. (c) Schultz, N.;Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2005, 109, 11127.

Coordination of Rh(I) to the oxygen initiates the oxonia-Claisenrearrangement which proceeds via a dissociative-TS with 23.4 kcal/molbarrier (See FIG. 2, TS2). Coordination of Rh(I) with the alkyne directsrearrangement via a very low 9.7 kcal barrier (See FIG. 3, TS3). Evenafter the Curtin-Hammett correction, the latter route offers the lowestenergy path for the Claisen rearrangement with the barrier of 17.7kcal/mol (See FIG. 3). For the stereoelectronic reasons for theendo-selectivity in metal-catalyzed reactions (“LUMO umpolung), see: (a)Alabugin, I. Gilmore, K.; Manoharan, M. J. Am. Chem. Soc. 2011, 133,12608. Reviews: (b) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111,6513. (c) Peterson, P. W.; Mohamed, R. K.; Alabugin, I. V. Eur. J. Org.Chem., 2013, 2013, 2505. Selected applications: (d) Zhao, J.; Hughes, C.O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436. (e) Byers, P. M.;Rashid, J. I.; Mohamed, R. K.; Alabugin, I. V. Org. Lett. 2012, 14,6032. (f) Hashmi, A. S. K.; Braun, I.; Rudolph, M.; Rominger, F.Organometallics 2012, 31, 644. (g) Naoe, S.; Suzuki, Y.; Hirano, K.;Inaba, Y.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2012, 77, 4907.(i) Hansmann, M. M.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew.Chem., Int. Ed. 2013, 52, 2593.

Although the interception of the pericyclic pathway is conceptuallyinteresting and increasingly utilized in the design of cascade organictransformations, the six-membered intermediate in the“cyclization-mediated pathway” is often elusive and its presence andlifetime depend on the intricate details of transition statecomplexation with the catalyst. Selected precedents for the interceptionof pericyclic pathways: Discovery of aborted pericyclic reactions: (a)Gilmore, K.; Manoharan, M.; Wu, J.; Schleyer, P. v. R; Alabugin, I. V.J. Amer. Chem. Soc. 2012, 134, 10584. Interrupted pericyclic reactions:(b) Navarro-Vazquez, A.; Prall, M.; Schreiner, P. R. Org. Lett. 2004, 6,2981. Recent reviews: (c) Graulich, N.; Hopf, H.; Schreiner, P. R. Chem.Soc. Rev. 2010, 39, 1503. (d) Mohamed, R. K.; Peterson, P. W.; Alabugin,I. V. Chem. Rev., 2013, http://dx.doi.org/10.1021/cr4000682. For thespecial properties of alkynes facilitating the design of such reactions,see: Alabugin, I. V.; Gold, B. J. Org. Chem. 2013, 78,http://pubs.acs.org/doi/abs/10.1021/jo401091w. For example, we had shownin our earlier work on Au-catalyzed rearrangement how coordination of Austabilizes TS for the subsequent Grob-type fragmentation into theallene-aldehyde product to the extent that the intermediate correspondsto a shallow inflection at the potential energy surface. On the otherhand, Siebert and Tantillo found that a combination of transition-statecomplexation with resonance stabilization converts a TS into a cyclicintermediate in Pd-promoted Cope rearrangement. See Siebert, M. R.;Tantillo, D. J. J. Am. Chem. Soc. 2007, 129, 8686.

At the M05-2X/LANL2DZ level of theory, we did not find an energy minimumcorresponding to the six-membered organorhodium intermediate in theparent system (FIG. 3). Further mechanistic exploration is needed tofully understand the subtleties of this transformation since the (E,Z)-stereochemistry of double bonds in the dienal is fully consistentwith the suggested transformation of the six-membered intermediate. Thestereochemistry of the two double bonds in 2a and 2b was confirmed byselective gradient-enhanced 1D NOESY (SELNOGP) and comparison to theknown proton NMRs of the (E, Z) dienals 2a, 7, 8, 10 and 11. See (a)Makin, S. M.; Mikerin, I. E.; Shavrygina, O. A.; Ermakova, G. A.;Arshava, B. M. Zh. Org. Khim. 1984, 20, 2317. (b) Kann, N.; Rein, T.;Akermark, B.; Helquist, P. J. Org. Chem. 1990, 55, 5312. (c) Gravel, D.;Leboeuf, C. Can. J. Chem. 1982, 60, 574. (d) Taylor, R. J. K.; Hemming,K.; De Medeiros, E. F. J. Chem. Soc., Perkin Trans. 1 1995, 2385. (e)Bellassoued, M.; Malika, S. Bull. Soc. Chim. Fr., 1997, 134, 115.

In summary, Rh-catalyzed Claisen rearrangement followed bystereoselective hydrogen transfer converts propargyl vinyl ethers intothe target (E, Z)-dienals in high yields, excellent stereoselectivityand with minimal waste. The reaction tolerates steric hindrance and iscompatible with substituents of different electronic demand. This atomeconomical method yields complex and stereochemically defined dienals inonly three steps from commercially available aldehydes.

Examples

The following non-limiting examples are provided to further illustratethe present invention.

General Consideration.

All commercially procured chemicals were used as received.Dichloromethane (DCM), tetrahydrofuran (THF), triethylamine (Et₃N),diethyl ether (Et₂O) were distilled from calcium hydride (CaH₂).Tetrahydrofuran (THF) was distilled from lithium aluminum hydride (LAH).Reagent grade solvents were used for solvent extraction and organicextracts were dried over anhydrous sodium sulfate (Na₂SO₄). Silica gel60 (230-400 mesh ASTM) and neutral alumina were used for FlashChromatography with dry hexane/ethyl acetate eluent system. ¹H NMR and¹³Cspectra were recorded on 500 MHz Bruker or 300 MHz Varianspectrometers. The proton chemical shifts (δ) are reported as parts permillion relative to 2.09 quintet ppm for CD₃C₆D₅, 5.32 for CD₂Cl₂ and7.27 for CDCl₃. The carbon chemical shifts (δ) were reported as thecenterline of triplet at 77.0 ppm for CDCl₃ and quintet at 54.00 ppm forCD₂Cl₂. Infrared spectra were recorded on sodium chloride plates using aPerkin-Elmer FT-IR Paragon 1000 spectrometer and frequencies werereported as reciprocal of centimeters (cm⁻¹). Mass spectra were recordedusing a Jeol JMS-600 instrument. The computations were performed usingGaussian03 on High Performance Computing facility (HPC) at Florida StateUniversity.

Computational Study

All geometries were optimized at the B3LYP/LANL2DZ and M05-2X/LANL2DZlevels which frequently performs well for the transition metal compounds(e.g. Xia, Y.; Dudnik, A. S.; Gevorgyan, V.; Li, Y. J Am Chem Soc. 2008,130, 6940-6941 and Soriano, E.; Marco-Contelles, J. Acc. Chem. Res.2009, 42, 1026-1036) using Gaussian 03 program (see reference). ForceField calculation indicated that optimized structures were found to betrue minima with no imaginary frequency.

Gaussian 03, Revision E.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel,G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T.Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J.Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A.Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.Hasegawa, M. Ishida, T. Nakajima, Y. Honda, 0. Kitao, H. Nakai, M.Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J.Jaramillo, R. Gomperts, R. E. Stratmann, 0. Yazyev, A. J. Austin, R.Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A.Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A.D. Daniels, M. C. Strain, 0. Farkas, D. K. Malick, A. D. Rabuck, K.Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S.Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P.Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham,C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson,W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc.,Wallingford, Conn., 2003.

General Procedure for Vinylation of Alcohols:

To a 0.1 M solution of 1-phenylbut-2-yn-1-ol (1 mmol) in ethyl vinylether was added 0.6 mmol of mercuric acetate. The reaction mixture wasrefluxed at 45° C. for 12 hours before quenching with a saturatedaqueous sodium carbonate solution. The organic phase was extracted usingdiethyl ether and dried over anhydrous potassium carbonate. The solventwas removed under vacuum and the crude vinyl ether was purified onalumina gel column using hexane as an eluent. Vinyl ether 1 was obtainedin 60% yield (0.1 g).

Vinyl Ether 14: (1-(vinyloxy)but-2-yn-1-yl)benzene

¹H NMR (500 MHz, CD₂Cl₂) δ: 7.55 (m, 2H), 7.43 (m, 3H), 6.56 (dd,J=14.1, 6.6 Hz, 1H), 5.54 (q, J=2.1 Hz, 1H), 4.51 (dd, J=14.1, 1.8 Hz,1H), 4.21 (dd, J=6.6, 1.8 Hz, 1H), 1.97 (d, J=2.2 Hz, 3H). ¹³C NMR (125MHz, CD₂Cl₂) δ: 149.6, 138.4, 128.5, 128.5, 127.2, 89.8, 84.9, 76.2,71.1, 3.4. HRMS (EI+) Calcd. For C₁₂H₁₂O (M⁺): 172.0888. Found:172.0875.

Vinyl Ether 15: 1-chloro-4-(1-(vinyloxy)hept-2-yn-1-yl)benzene

¹H NMR (500 MHz, CD₂Cl₂) δ: 7.46 (m, 2H), 7.37 (m, 2H), 6.50 (dd,J=14.2, 6.6 Hz, 1H), 5.49 (t, J=2.0 Hz, 1H), 4.46 (dd, J=14.1, 1.9 Hz,1H), 4.17 (dd, J=6.6, 1.9 Hz, 1H), 2.37 (s, 1H), 2.29 (td, J=7.2, 2.1Hz, 2H), 1.52 (m, 2H), 1.42 (m, 2H), 0.91 (t, J=7.3 Hz, 3H). ¹³C NMR(125 MHz, CD₂Cl₂) δ: 149.4, 137.1, 134.2, 128.7, 128.6, 90.2, 89.9,76.5, 70.3, 30.53, 21.9, 18.4, 13.3. HRMS (EI+) Calcd. For C₁₅H₁₇OCl(M⁺): 248.0968. Found: 248.0954.

Vinyl Ether 16: 4-(1-(vinyloxy)hept-2-yn-1-yl)benzonitrile

¹H NMR (500 MHz, CD₂Cl₂) δ: 7.72 (m, 2H), 7.67 (m, 2H), 6.55 (dd,J=14.1, 6.6 Hz, 1H), 5.60 (t, J=1.9 Hz, 1H), 4.52 (dd, J=14.1, J=2.0 Hz,1H), 4.24 (dd, J=6.6, 2.0 Hz, 1H), 2.33 (td, J=7.2, 2.1 Hz, 2H), 1.56(m, 2H), 1.45 (m, 2H), 0.95 (t, J=7.3 Hz, 3H). ¹³C NMR (125 MHz, CD₂Cl₂)δ: 149.2, 143.4, 132.3, 127.8, 118.5, 112.3, 90.6, 90.6, 30.4, 21.91,18.3, 13.3. HRMS (EI+) Calcd. For C₁₆H₁₂ON (M⁺): 239.1310. Found:239.1299.

Vinyl Ether 17: (3-(vinyloxy)prop-1-yne-1,3-diyl)dibenzene

¹H NMR (500 MHz, CD₂Cl₂) δ: 7.64 (m, 2H), 7.53 (m, 2H), 7.49-7.36 (m,6H), 6.63 (dd, J=14.2, 6.6 Hz, 1H), 5.80 (s, 1H), 4.59 (dd, J=14.1, 1.9Hz, 1H), 4.27 (dd, J=6.6, 2.0 Hz, 1H). ¹³C NMR (125 MHz, CD₂Cl₂) δ:149.6, 137.8, 131.7, 128.9, 128.8, 128.6, 128.4, 127.4, 122.0, 90.3,88.1, 85.9, 71.2. HRMS (EI+) Calcd. For C₁₂H₁₄O (M⁺): 234.1045 Found:234.1040.

Vinyl Ether 18: 1,3,5-trimethyl-2-(1-(vinyloxy)but-2-yn-1-yl)benzene

¹H NMR (300 MHz, CD₂Cl₂) δ: 6.80 (s, 2H), 6.43 (dd, J=14.1, 6.6 Hz, 1H),5.84 (q, J=2.3 Hz, 1H), 4.43 (dd, J=14.1, 1.8 Hz, 1H), 4.11 (dd, J=6.6,1.8 Hz, 1H), 2.46 (s, 6H), 2.30 (s, 3H), 1.90 (d, J=2.3 Hz, 3H). ¹³C NMR(125 MHz, CD₂Cl₂) δ: 149.6, 137.9, 136.5, 131.8, 129.8, 89.2, 83.4,75.8, 67.3, 20.57, 19.9, 3.4. HRMS (EI+) Calcd. For C₁₅H₁₈O (M⁺):214.1358 Found: 214.1364.

Vinyl Ether 19: 1-methyl-4-(1-(vinyloxy)but-2-yn-1-yl)benzene

¹H NMR (500 MHz, CD₂Cl₂) δ: 7.42 (m, 2H), 7.25 (m, 2H), 6.53 (dd,J=13.8, 6.5 Hz, 1H), 5.49 (q, J=2.0 Hz, 1H), 4.48 (dd, J=14.0, 1.8 Hz,1H), 4.17 (dd, J=6.6, 1.8 Hz, 1H), 2.40 (s, 3H), 1.96 (d, J=2.3 Hz, 3H).¹³C NMR (125 MHz, CD₂Cl₂) δ: 149.6, 138.5, 135.5, 129.13, 127.2, 89.8,84.7, 76.4, 71.0, 20.9, 3.4. HRMS (EI+) Calcd. For C₁₃H₁₄O (M⁺):186.1045 Found: 186.1041.

Vinyl Ether 20: 4-(vinyloxy)oct-2-yne

¹H NMR (300 MHz, CD₂Cl₂) δ: 6.44 (dd, J=14.3, 7.0 Hz, 1H), 4.38 (m, 1H),4.36 (dd, J=13.9, 1.5 Hz, 1H), 4.08 (dd, J=6.5, 1.5 Hz, 1H), 1.86 (d,1.9 Hz, 3H), 1.73 (dtd, 8.3, 6.7, 5.6 Hz, 2H), 1.39 (m, 2H), 0.93 (t,7.4 Hz, 3H). ¹³C NMR (75 MHz, CD₂Cl₂) δ: 146.9, 85.6, 79.1, 74.2, 66.2,41.0, 32.3, 24.1, 19.1, 10.6. HRMS (EI+) Calcd. For C₁₀H₁₆O (M⁺):152.1201 Found: 152.1190.

Vinyl Ether 21: 5,5-dimethyl-4-(vinyloxy)hex-2-yne

¹H NMR (500 MHz, CD₂Cl₂) δ: 6.42 (dd, J=14.2, 6.6 Hz, 1H), 5.35 (q,J=2.1 Hz, 1H), 4.34 (dd, J=14.2, 1.7 Hz, 1H), 4.02 (dd, J=6.6, 2.1 Hz,1H), 1.85 (d, J=2.1 Hz, 3H), 0.98 (s, 9H). ¹³C NMR (75 MHz, CD₂Cl₂) δ:150.9, 88.2, 82.9, 78.1, 75.9, 35.4, 25.3, 3.2. HRMS (EI+) Calcd. forC₁₀H₁₆O (M⁺): 152.1201. Found: 152.1176.

Vinyl Ether 22: 1-(1-(vinyloxy)but-2-yn-1-yl)cyclohex-1-ene

¹H NMR (500 MHz, CD₂Cl₂) δ: 6.42 (dd, J=14.1, 6.6 Hz, 1H), 5.94 (m, 1H),4.77 (m, 1H), 4.40 (dd, J=14.1, 1.7 Hz, 1H), 4.09 (dd, J=6.6, 2.0 Hz,1H), 2.24-2.16 (m, 2H), 2.11 (m, 4H), 1.98 (m, 2H), 1.91 (d, J=2.1 Hz,3H), 1.68 (m, 2H), 1.62 (m, 2H). ¹³C NMR (125 MHz, CD₂Cl₂) δ: 149.5,134.9, 126.6, 89.2, 83.6, 73.9, 25.0, 24.13, 22.2, 3.3. HRMS (EI+)Calcd. For C₁₂H₁₆O (M⁺):176.1201. Found: 176.1199.

Vinyl Ether 23: 2-(1-(vinyloxy)but-2-yn-1-yl)furan

¹H NMR (300 MHz, CD₂Cl₂) δ: 7.44 (dd, J=1.9, 0.8 Hz, 1H), 6.52 (dt,J=3.4, 0.7 Hz, 1H), 6.49 (dd, J=14.1, 6.6 Hz, 1H), 6.39 (dd, 3.5, 1.9Hz, 1H), 5.51 (q, J=2.1 Hz, 1H), 4.45 (dd, J=14.0, 1.9 Hz, 1H), 4.16(dd, J=6.6, 1.8 Hz, 1H), 1.92 (d, J=2.3 Hz, 3H). ¹³C NMR (125 MHz,CD₂Cl₂) δ: 150.9, 148.9, 143.4, 110.4, 109.4, 90.2, 84.2, 73.6, 64.4,3.3. HRMS (EI+) Calcd. For C₁₀H₁₀O₂ (M⁺): 162.0681 Found: 162.0683.

Vinyl Ether 24:1,3,3-trimethyl-2-(1-(vinyloxy)but-2-yn-1-yl)cyclohex-1-ene

¹H NMR (500 MHz, CD₂Cl₂) δ: 6.45 (dd, J=14.1, 6.6 Hz, 1H), 4.96 (q,J=2.3 Hz, 1H), 4.43 (dd, J=14.1, 1.5 Hz, 1H), 4.11 (dd, J=6.5, 1.6 Hz,1H), 2.03 (t, J=6.2 Hz, 1H), 1.89 (s, 3H), 1.88 (d, J=1.5 Hz, 3H), 1.6(m, 2H), 1.48 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H). ¹³C NMR (125 MHz,CD₂Cl₂) δ: 150.2, 134.9, 134.9, 88.8, 82.1, 77.6, 66.8, 39.4, 34.5,33.5, 28.2, 27.2, 20.7, 19.2, 3.4. HRMS (EI+) Calcd. For C₁₅H₂₂O (M⁺):218.1671 Found: 218.1682.

Vinyl Ether 25: (3-cyclopropyl-3-(vinyloxy)prop-1-yn-1-yl)benzene

¹H NMR (500 MHz, CD₂Cl₂) δ: 7.43 (m, 2H), 7.34 (m, 3H), 6.54 (dd,J=14.1, 6.6 Hz, 1H), 4.51 (d, J=6.4 Hz, 1H), 4.45 (dd, J=14.1, 1.8 Hz,1H), 4.15 (dd, J=6.6, 1.8 Hz, 1H), 1.37 (m, 1H), 0.62 (m, 3H), 0.53 (m,1H). ¹³C NMR (125 MHz, CD₂Cl₂) δ: 149.9, 131.7, 128.7, 128.3, 122.2,89.4, 86.3, 85.1, 72.8, 14.8, 2.9, 1.8. HRMS (EI+) Calcd. For C₁₄H₁₄O(M⁺): 198.1045 Found: 198.1046.

Vinyl Ether 26:1-(3-cyclohexyl-3-(vinyloxy)prop-1-yn-1-yl)cyclohex-1-ene

¹H NMR (500 MHz, CD₂Cl₂) δ: 6.47 (dd, J=14.1, 6.9 Hz, 1H), 6.14 (tt,J=3.5, 1.6 Hz, 1H), 4.40 (dd, J=14.3, 2.0 Hz, 1H), 4.34 (d, J=6.3 Hz,1H), 4.10 (dd, J=6.6, 1.9 Hz, 1H), 2.17-2.09 (m, 4H), 1.88 (m, 2H), 1.79(m, 2H), 1.75-1.58 (m, 6H), 1.36-1.08 (m, 5H). ¹³C NMR (125 MHz, CD₂Cl₂)δ: 150.3, 135.3, 120.1, 88.8, 88.7, 83.4, 74.2, 42.6, 29.2, 28.7, 28.3,26.4, 25.9, 25.9, 25.6, 22.3, 21.5. HRMS (EI+) Calcd. For C₁₇H₂₄O (M⁺):244.1827 Found: 244.1828.

General Procedure for Propargyl Claisen Rearrangement:

A stock solution of [Rh(CO)₂Cl]₂ (6 mg, 0.015 mmol) was prepared in 0.3mL toluene. To a solution of vinyl ether 1 (0.1 mmol) in 0.1 M tolueneunder argon atmosphere was added 0.1 mL of a standard solution of[Rh(CO)₂Cl]₂. The reaction mixture was stirred for 12 to 24 hours at 50°C. Upon complete consumption of vinyl ether 1, the products wereisolated using alumina column chromatography. Silica column gave mixtureof EZ/EE ratios ranging from 100:3 to 100:20. The isolated productsunderwent slow isomerization at room temperature.

Vinyl ether: 1-methoxy-4-(1-(vinyloxy)hept-2-yn-1-yl)benzene

Dienal 3

Using the general procedure described above,1-methoxy-4-(1-(vinyloxy)hept-2-yn-1-yl)benzene gave 85% (20.7 mg) ofDienal 3.¹H NMR (500 MHz, CD₂Cl₂) E, Z δ: 10.19 (d, J=7.9 Hz, 1H), 7.53(d, J=16.1 Hz, 1H), 7.42 (m, 2H), 6.90 (d, J=16.1 Hz, 1H), 6.85 (m, 2H),5.80 (dt, J=7.9, 0.5 Hz, 1H), 3.76 (s, 3H), 2.43 (td, J=7.7, 0.6 Hz,2H), 1.52 (m, 2H), 1.35 (m, 2H), 0.89 (t, J=7.4 Hz, 3H). E, E δ: 10.02(d, J=8.2 Hz, 1H), 7.42 (m, 2H), 6.99 (d, J=16.2 Hz, 1H), 6.85 (m, 2H),6.64 (d, J=16.2 Hz, 1H), 5.91 (d, J=8.2 Hz, 1H), 3.75 (s, 3H), 2.43 (t,J=7.7, 2H), 1.52 (m, 2H), 1.35 (m, 2H), 0.90 (t, J=7.4 Hz, 3H). ¹³C NMR(125 MHz, CD₂Cl₂) δ: 190.1, 160.6, 159.2, 135.9, 128.7, 127.1, 120.5,55.4, 34.2, 31.3, 22.6, 13.7.

Dienal 4: (Z)-3-((E)-4-chlorostyryl)hept-2-enal

Using the general procedure described above, 0.1 mmol (24.8 mg) vinylether 15 gave 91% (22.5 mg) of dienal 4. ¹H NMR (500 MHz, CD₂Cl₂) E, Zδ: 10.28 (d, J=7.8 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H), 7.52 (m, 2H), 7.41(m, 2H), 6.99 (d, J=16.0 Hz, 1H), 5.94 (dt, J=7.7, 0.7 Hz, 1H), 2.54(td, J=7.7, 0.8 Hz, 2H), 1.62 (m, 2H), 1.45 (tq, J=7.5, 7.4 Hz, 2H),0.99 (t, J=7.3 Hz, 3H). ¹³C NMR (125 MHz, CD₂Cl₂) δ: 190.1, 158.3,134.9, 134.7, 134.6, 129.1, 128.5, 123.5, 34.1, 31.1, 22.6, 13.6. HRMS(EI+) Calcd. For C₁₅H₁₇OCl (M⁺): 248.0968. Found: 248.0969.

Dienal 5: 4-((1E,3Z)-3-(2-oxoethylidene)hept-1-en-1-yl)benzonitrile

Using the general procedure described above, 0.1 mmol (24.0 mg) vinylether 16 gave 87% (21 mg) of dienal 5. ¹H NMR (500 MHz, CD₂Cl₂) E, Z δ:10.27 (d, J=7.5 Hz, 1H), 7.83 (d, J=16.3 Hz, 1H), 7.72 (m, 2H), 7.66 (m,2H), 7.02 (d, J=16.1 Hz, 1H), 6.03 (dt, J=7.6, 0.6 Hz, 1H), 2.55 (td,J=7.7, 0.6 Hz, 2H), 1.62 (m, 2H), 1.46 (tq, J=7.6, 7.4 Hz, 2H), 0.99 (t,J=7.4 Hz, 3H). ¹³C NMR (125 MHz, CD₂Cl₂) δ: 189.9, 157.5, 140.6, 133.9,132.6, 129.0, 127.6, 126.42, 118.6, 112.0, 30.0, 30.9, 22.6, 13.6. HRMS(EI+) Calcd. For C₁₆H₁₇ON (M⁺): 239.1310. Found: 239.1315.

Dienal 6: (2Z,4E)-3-methyl-5-(4-(trifluoromethyl)phenyl)penta-2,4-dienal

Using the general procedure described above, 0.1 mmol (24.0 mg)1-(trifluoromethyl)-4-(1-(vinyloxy)but-2-yn-1-yl)benzene gave 90% (22mg) of dienal 6. ¹H NMR (500 MHz, CD₂Cl₂) δ: 10.29 (d, J=7.9 Hz, 1H),7.93 (d, J=16.0 Hz, 1H), 7.65 (m, 4H), 7.03 (d, J=16.0 Hz, 1H), 5.98(dq, J=8.5, 1.2 Hz, 1H), 2.21 (d, J=1.2 Hz, 3H). ¹³C NMR (125 MHz,CD₂Cl₂) δ 189.6, 153.0, 139.7, 134.7, 129.6, 127.5, 125.9, 125.8, 125.7,20.9. HRMS (EI+) Calcd. For C₁₃H₁₁F₃O (M⁺), 240.0762 Found: 240.0752.

Dienal 9: (2Z,4E)-3-methyl-5-(p-tolyl)penta-2,4-dienal

Using the general procedure described above, 0.1 mmol (19 mg) vinylether 19 gave 92% (17 mg) of dienal 9. ¹H NMR (500 MHz, CD₂Cl₂) δ: 10.34(d, J=8.2 Hz, 1H), 7.87 (d, J=16.0 Hz, 1H), 7.48 (m, 2H), 7.25 (m, 2H),7.03 (d, J=16.0 Hz, 1H), 5.94 (dq, J=7.8, 1.1 Hz, 1H), 2.41 (s, 3H),2.24 (d, J=1.2 Hz, 3H). ¹³C NMR (125 MHz, CD₂Cl₂) δ: 189.7, 154.3,139.6, 136.6, 133.3, 129.6, 128.3, 127.3, 122.3, 21.1, 20.9. HRMS (EI+)Calcd. For C₁₃H₁₄O (M⁺): 186.1045. Found: 186.1040.

Additional dienals were prepared according to the method of the presentinvention:

Makin, S. M.; Mikerin, I. E.; Shavrygina, O. A.; Ermakova, G. A.;Arshava, B. M. Zh. Org. Khim. 1984, 20, 2317. (b) Kann, N.; Rein, T.;Akermark, B.; Helquist, P. J. Org. Chem. 1990, 55, 5312. (c) Gravel, D.;Leboeuf, C. Can. J. Chem. 1982, 60, 574. (d) Taylor, R. J. K.; Hemming,K.; De Medeiros, E. F. J. Chem. Soc., Perkin Trans. 1 1995, 2385. (e)Bellassoued, M.; Malika, S. Bull. Soc. Chim. Fr., 1997, 134, 115.

Dienal 2a: (2Z,4E)-3-methyl-5-phenylpenta-2,4-dienal

Using the general procedure described above, 0.1 mmol (17.2 mg)(1-(vinyloxy)but-2-yn-1-yl)benzene gave 85% (14.5 mg) of dienal 2a. ¹HNMR (500 MHz, Toluene-d₈) E, Z δ: 10.05 (d, J=7.5 Hz, 1H), 7.20-7.03 (m,5H), 7.53 (d, J=15.9, 1H), 6.52 (d, J=16.1 Hz, 1H), 5.71 (dq, J=7.6, 1.1Hz, 1H), 1.63 (d, J=1.1 Hz, 3H).

Dienal 7: (2E,4E)-3,5-diphenylpenta-2,4-dienal

Using the general procedure described above, 0.1 mmol (24.8 mg) vinylether 20 gave 78% (18.5 mg) of dienal 7. ¹H NMR (500 MHz, Toluene-d₈) E,Z δ: 10.06 (d, J=7.3 Hz, 1H), 7.45 (d, J=15.7, 1H), 7.15-7.01 (m, 10H),6.55 (d, J=16.0 Hz, 1H), 6.03 (d, J=7.3, 1H). ¹³C NMR (125 MHz,Toluene-d₈) δ: 188.7, 156.4, 140.4, 139.3, 135.9, 129.7, 129.0, 128.9,128.5, 128.4, 127.9, 127.3, 123.3.

Dienal 10: (2Z,4E)-3-methylnona-2,4-dienal

Using the general procedure described above, 0.1 mmol (24.8 mg) vinylether 20 gave 91% (22.5 mg) of dienal 10. ¹H NMR (500 MHz, CDCl₃) E, Zδ: 10.18 (d, J=8.2 Hz, 1H), 7.08 (d, J=15.9 Hz, 1H), 6.21 (ddd, J=15.8,8.0, 7.2 Hz, 1H), 5.82 (d, J=8.3 Hz, 1H), 2.25 (m, 2H), 1.46 (m, 2H),1.37 (m, 2H), 0.94 (t, J=7.5 Hz, 3H).

Dienal 11: (2Z,4E)-3,6,6-trimethylhepta-2,4-dienal

Using the general procedure described above, 0.1 mmol (24.8 mg) vinylether 21 gave 91% (22.5 mg) of dienal 11. ¹H NMR (500 MHz, Toluene-d₈)E, Z δ: 10.12 (d, J=8.0 Hz, 1H), 6.85 (d, J=15.8 Hz, 1H), 5.84 (dd,J=16.1, 0.67 Hz, 1H), 5.67 (dm, J=8 Hz, 1H), 1.58 (d, J=1.2 Hz, 3H),0.89 (s, 9H). ¹³C NMR (125 MHz, Toluene-d₈) δ: 188.2, 152.9, 149.0,127.9, 120.7, 33.5, 28.7, 20.6.

Dienal 12: (2Z,4E)-5-(cyclohex-1-en-1-yl)-3-methylpenta-2,4-dienal

Using the general procedure described above, 0.1 mmol (24.8 mg) vinylether 22 gave 91% (22.5 mg) of dienal 12. ¹H NMR (500 MHz, CDCl₃) E, Zδ: 10.25 (d, J=8.0 Hz, 1H), 7.19 (d, J=16.0 Hz, 1H), 6.67 (d, J=16.0 Hz,1H), 6.11 (m, 1H), 5.88 (d, J=8 Hz, 1H), 2.27 (m, 4H), 2.15 (d, J=1.1Hz, 3H), 1.77 (m, 2H), 1.69 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ: 190.1,155.4, 140.8, 136.3, 135.9, 127.6, 119.6, 26.5, 24.4, 22.3, 21.3.

Dienal 13: (2Z,4E)-5-(furan-2-yl)-3-methylpenta-2,4-dienal

Using the general procedure described above, 0.1 mmol (16.2 mg) vinylether 22 gave 95% (15.5 mg) of dienal 12. ¹H NMR (500 MHz, CDCl₃) E, Zδ: 10.06 (d, J=7.5 Hz, 1H), 7.60 (d, J=15.8 Hz, 1H), 6.93 (d, J=1.6 Hz,1H), 6.23 (d, J=15.8 Hz, 1H), 6.60 (m, 2H), 5.68 (dq, J=7.6, 1.1 Hz,1H), 1.43 (d, J=1.1 Hz, 3H), 1.77 (m, 2H), 1.69 (m, 2H). ¹³C NMR (125MHz, CDCl₃) δ: 188.3, 152.4, 151.4, 143.4, 128.8, 121.9, 111.8, 111.5,198.

Dienal 8: (2Z,4E)-5-(furan-2-yl)-3-methylpenta-2,4-dienal

Using the general procedure described above, 0.1 mmol (21.4 mg) vinylether 18 gave 82% (17.5 mg) of dienal 8. ¹H NMR (500 MHz, CDCl₃) E, Z δ:10.23 (d, J=7.9 Hz, 1H), 7.36 (d, J=16.4 Hz, 1H), 7.10 (d, J=16.4 Hz,1H), 6.96 (s, 2H), 6.00 (dq, J=8.1, 1.2 Hz, 1H), 2.37 (s, 6H), 2.34 (s,3H), 2.28 (d, J=1.2 Hz, 3H). E, E 6: 10.02 (d, J=8.2 Hz, 1H), 7.05 (d,J=12.2 Hz, 1H), 6.89 (s, 2H), 6.83 (d, J=12.4 Hz, 1H), 5.80 (dq, J=8.3,1.2 Hz, 1H), 2.31 (s, 3H), 2.22 (s, 6H), 1.71 (d, J=1.2 Hz, 3H).

Mercury Poisoning Experiments.

The mercury poisoning experiments were performed to determine the roleof nanoclusters or colloids in the proton rearrangement. The 0.1Msolution of allene-aldehyde (0.1 mmols, 18.6 mg) and 5% Rh(I)-dimer(0.005 mmols, 2 mg) in toluene was monitored until the formation of 20%(E, Z)-dienal at which point the large excess of elemental mercury (4gm) was added. The reaction was stirred vigorously for 2 hours beforetaking the proton NMR spectrum. Apart from reaction inhibition, weobserved that the elemental mercury, instead of coalescing, stayed inthe dispersed phase.

When introducing elements of the present invention or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above products and methodswithout departing from the scope of the invention, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

What is claimed is:
 1. A method to synthesize an (E,Z)-dienal compoundhaving structure (V), the method comprising: contacting a compoundhaving structure (III) with a catalyst comprising Rh(I) to therebyprepare the compound having structure (V); wherein the compounds havingstructures (III) and (V) have the following structures:

wherein R₁ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino; and R₂ is selectedfrom the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl,amino, and C₁₋₁₂ alkylamino.
 2. The method of claim 1 wherein thecompound having structure (III) is synthesized by contacting a compoundhaving structure (I) and a compound having structure (II) according tothe following sequence:

wherein R₁ and R₂ are as defined in claim
 1. 3. The method of claim 1wherein the compound having structure (III) is synthesized by contactinga compound having structure (I) and a compound having structure (II)according to the following sequence:

wherein R₁ and R₂ are as defined in claim
 1. 4. The method of claim 1wherein R₁ comprises a C₆₋₂₄ aryl or C₃₋₁₈ heteroaryl.
 5. The method ofclaim 1 wherein R₁ is substituted with a substituent selected from thegroup consisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halo,hydroxy, cyano, C₁₋₁₂ alkoxy, nitro, sulfinyl, sulfonyl, amino, an C₁₋₁₂alkylamino.
 6. The method of claim 1 wherein the compound havingstructure (III) is contacted with a homogenous catalyst comprisingRh(I), and the preparation of the compound having structure (V) convertsthe homogenous catalyst comprising Rh(I) into a Rh(I)-nanocluster.
 7. Amethod to synthesize an (E,Z)-dienal compound having structure (V), themethod comprising: contacting a compound having structure (IV) with acatalyst comprising Rh(I) to thereby prepare the compound havingstructure (V); wherein the compounds having structures (IV) and (V) havethe following structures:

wherein R₁ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino; and R₂ is selectedfrom the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl,amino, and C₁₋₁₂ alkylamino.
 8. The method of claim 7 wherein R₁comprises a C₆₋₂₄ aryl or C₃₋₁₈ heteroaryl.
 9. The method of claim 7wherein R₁ is substituted with a substituent selected from the groupconsisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halo,hydroxy, cyano, C₁₋₁₂ alkoxy, nitro, sulfinyl, sulfonyl, amino, an C₁₋₁₂alkylamino.
 10. The method of claim 7 wherein the catalyst comprisingRh(I) comprises an Rh(I)-nanocluster.
 11. The method of claim 7 whereinthe compound having structure (IV) is synthesized by contacting acompound having structure (III) with a catalyst comprising Rh(I):

wherein R₁ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino; and R₂ is selectedfrom the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl,amino, and C₁₋₁₂ alkylamino.
 12. The method of claim 11 wherein thecatalyst comprising Rh(I) comprises a homogenous catalyst.
 13. Themethod of claim 11 wherein the compound having structure (III) issynthesized by contacting a compound having structure (I) and a compoundhaving structure (II) according to the following sequence:

wherein R₁ and R₂ are as defined in claim
 11. 14. The method of claim 11wherein the compound having structure (III) is synthesized by contactinga compound having structure (I) and a compound having structure (II)according to the following sequence:

wherein R₁ and R₂ are as defined in claim
 11. 15. A method of preparinga compound having structure (III), the method comprising: contacting acompound having structure (I) and a compound having structure (II) inthe presence of a strong base; wherein the compounds having structures(I), (II), and (III) have the following structures:

wherein R₁ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino; and R₂ is selectedfrom the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl,amino, and C₁₋₁₂ alkylamino.
 16. The method of claim 15 wherein R₁comprises a C₆₋₂₄ aryl or C₃₋₁₈ heteroaryl.
 17. The method of claim 15wherein R₁ is substituted with a substituent selected from the groupconsisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halo,hydroxy, cyano, C₁₋₁₂ alkoxy, nitro, sulfinyl, sulfonyl, amino, an C₁₋₁₂alkylamino.
 18. A method to synthesize an allene-aldehyde compoundhaving structure (IV), the method comprising: contacting a compoundhaving structure (III) with a catalyst comprising Rh(I) to therebyprepare the compound having structure (IV); wherein the compounds havingstructures (III) and (IV) have the following structures:

wherein R₁ is selected from the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄aryl, C₃₋₁₈ heteroaryl, amino, and C₁₋₁₂ alkylamino; and R₂ is selectedfrom the group consisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl,amino, and C₁₋₁₂ alkylamino.
 19. The method of claim 18 wherein R₁comprises a C₆₋₂₄ aryl or C₃₋₁₈ heteroaryl.
 20. The method of claim 18wherein R₁ is substituted with a substituent selected from the groupconsisting of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₃₋₁₂ cycloalkenyl, C₆₋₂₄ aryl, C₃₋₁₈ heteroaryl, halo,hydroxy, cyano, C₁₋₁₂ alkoxy, nitro, sulfinyl, sulfonyl, amino, an C₁₋₁₂alkylamino.
 21. The method of claim 18 wherein the catalyst comprisingRh(I) comprises a homogenous catalyst.